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Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML

Rijal, Sewa, Fleming, Shaun, Cummings, Nik, Rynkiewicz, Natalie K., Ooms, Lisa M., Nguyen, Nhu-Y. N., Teh, Tse-Chieh, Avery, Sharon, McManus, Julie F., Papenfuss, Anthony T., McLean, Catriona, Guthridge, Mark A., Mitchell, Christina A. and Wei, Andrew H. 2015, Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML, Blood, vol. 125, no. 18, pp. 2815-2824, doi: 10.1182/blood-2014-09-603555.

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Title Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML
Author(s) Rijal, Sewa
Fleming, Shaun
Cummings, Nik
Rynkiewicz, Natalie K.
Ooms, Lisa M.
Nguyen, Nhu-Y. N.
Teh, Tse-Chieh
Avery, Sharon
McManus, Julie F.
Papenfuss, Anthony T.
McLean, Catriona
Guthridge, Mark A.ORCID iD for Guthridge, Mark A. orcid.org/0000-0002-0536-3471
Mitchell, Christina A.
Wei, Andrew H.
Journal name Blood
Volume number 125
Issue number 18
Start page 2815
End page 2824
Total pages 10
Publisher American Society of Hematology
Place of publication Washington, D. C.
Publication date 2015
ISSN 0006-4971
1528-0020
Summary Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry–based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.
Language eng
DOI 10.1182/blood-2014-09-603555
Indigenous content off
Field of Research 1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
HERDC Research category C1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30132333

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.